Spatial navigation deficits — overlooked cognitive marker for preclinical Alzheimer disease?


Detection of incipient Alzheimer disease (AD) pathophysiology is critical to identify preclinical individuals and target potentially disease-modifying therapies towards them. Current neuroimaging and biomarker research is strongly focused in this direction, with the aim of establishing AD fingerprints to identify individuals at high risk of developing this disease. By contrast, cognitive fingerprints for incipient AD are virtually non-existent as diagnostics and outcomes measures are still focused on episodic memory deficits as the gold standard for AD, despite their low sensitivity and specificity for identifying at-risk individuals. This Review highlights a novel feature of cognitive evaluation for incipient AD by focusing on spatial navigation and orientation deficits, which are increasingly shown to be present in at-risk individuals. Importantly, the navigation system in the brain overlaps substantially with the regions affected by AD in both animal models and humans. Notably, spatial navigation has fewer verbal, cultural and educational biases than current cognitive tests and could enable a more uniform, global approach towards cognitive fingerprints of AD and better cognitive treatment outcome measures in future multicentre trials. The current Review appraises the available evidence for spatial navigation and/or orientation deficits in preclinical, prodromal and confirmed AD and identifies research gaps and future research priorities.

Key points

  • Episodic memory has limited utility as a diagnostic and outcome measure for preclinical Alzheimer disease (AD).

  • Spatial navigation deficits have the potential to detect underlying pathophysiology in preclinical AD.

  • The brain areas affected earliest by AD pathophysiology are key nodes in the spatial navigation network.

  • Genetically at-risk individuals show altered spatial navigation patterns before any episodic memory symptom onset.

  • Spatial navigation is emerging as a potential cost-effective cognitive biomarker to detect AD in the preclinical stages, which has important implications for future diagnostics and treatment approaches.

  • Future spatial navigation benchmarks and standardization of spatial navigation tests are needed to realize this goal.

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Fig. 1: Egocentric and allocentric spatial coding.
Fig. 2: Anatomical illustration of AD-related neuropathological changes.
Fig. 3: The progressive pathophysiological changes that underlie navigational impairment in AD.


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M.H. and G.C. contributed to all aspects of the manuscript. J.L. and J.H. contributed to reviewing and editing the manuscript before submission. A.-M.M. contributed to writing of the manuscript.

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Correspondence to Michael Hornberger.

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Nature Reviews Neurology thanks T. Brandt, K. Possin and T. Wolbers for their contribution to the peer review of this work.

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Sea Hero Quest:


Episodic memory

One’s memory of events represented by aspects of the past not present in other memories, such as the time, place or social context.

Mild cognitive impairment

(MCI). Prodromal or intermediate stage between the expected cognitive decline of normal ageing and the more serious decline of dementia.

Egocentric navigation strategies

Egocentric self-centred navigation frames encode spatial information from the viewpoint of the navigator.

Allocentric navigation strategies

Allocentric strategies are based on the navigator’s perception of landmark positions relative to other landmarks.

Morris water maze

A test of spatial learning examining rodent ability to navigate from different starting locations around an open swimming arena to locate a submerged escape platform using only distal cues. For more information, see elsewhere149.

Significant memory concerns

(SMCs). Self-experienced persistent declines in cognitive abilities in comparison with a prior normal status; occur in the absence of objective impairment on standardized neuropsychological tests.

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Coughlan, G., Laczó, J., Hort, J. et al. Spatial navigation deficits — overlooked cognitive marker for preclinical Alzheimer disease?. Nat Rev Neurol 14, 496–506 (2018).

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